Regulation of Chromosome Segregation

准确的细胞分裂取决于染色体正确地分离到子细胞中。染色体分离的缺陷导致遗传不稳定性和非整倍性，这是癌症和出生缺陷的标志。染色体利用它们的动粒分离，动粒是组装在着丝粒DNA序列上并介导与有丝分裂纺锤体连接的特化蛋白质结构。虽然许多动粒成分已被确定，它是未知的动粒是如何调节介导染色体分离。本项目的长期目标是以酿酒酵母为模型系统，阐明动粒功能和染色体分离的调控和机制。动粒功能的一个关键调节因子是保守的Ip 11/aurora 2蛋白激酶。由于酵母Ip 11 p激酶的缺陷会导致非整倍体，而人类aurora 2激酶是一种致癌基因，因此对激酶的研究对于理解染色体分离和细胞转化都很重要。该提案的重点是Ip 11/aurora 2激酶和另一个保守的动粒组分，组蛋白H3变体Cse 4p，作为阐明染色体分离机制的一种手段。具体目标包括：1）分析Ip 11 p和Cse 4p组装成动粒以深入了解动粒组装的机制，2）研究Ip 11 p激酶的调节和底物以了解其如何调节染色体分离，3）研究Ip 11 p在纺锤体检查点中的作用，以及4）研究Ip 11 p和Cse 4p蛋白的动粒功能以了解动粒是如何调节的。这些研究将有助于更好地理解染色体分离的机制以及Ip 11/aurora 2激酶在基因组稳定性中的作用，研究可能阐明有关癌症产生的细节，并提供新的治疗途径。

Accurate cell division depends upon proper chromosome segregation into daughter cells. Defects in chromosome segregation lead to genetic instability and aneuploidy, hallmarkers of cancer and birth defects. Chromosomes segregate using their kinetochores, the specialized protein structures that are assembled on centromeric DNA sequences and mediate attachment to the mitotic spindle. Although many kinetochore components have been identified, it is unknown how kinetochores are regulated to mediate chromosome segregation. The long-term goal of this project is to elucidate the regulation and mechanisms of kinetochore function and chromosome segregation using the budding yeast Saccharomyces cerevisiae is a model system. A key regulator of kinetochore function is the conserved Ip11/aurora2 protein kinase. Since defects on the yeast Ip11p kinase lead to aneuploidy and the human aurora2 kinase is an oncogene, studies on the kinase are important to understanding both chromosome segregation and cellular transformation. This proposal This proposal focuses on the Ip11/aurora2 kinase and another conserved kinetochore component, the histone H3 variant Cse4p, as a means toward elucidating the mechanisms of chromosome segregation. The specific aims include: 1) analyzing Ip11p and Cse4p assembly into kinetochores to gain insight into mechanisms of kinetochore assembly, 2) investigating the regulation and substrates of the Ip11p kinase to understand how it regulates chromosome segregation, 3) examining the role of Ip11p in the spindle checkpoint, and 4) investigating the kinetochore functions of the Ip11p and Cse4p proteins to understand how kinetochores are regulated. These studies will lead to a better understanding of the mechanisms of chromosome segregation and the role of the Ip11/aurora2 kinase in genomic stability, studies may elucidate details about the generation of cancer and provide new avenues for therapy.